As a consequence, in addition to morality, there is a legal obligation to identify and use appropriate methods to replace, reduce, or refine experimental animal use. This obligation considers the internationally accepted 3Rs concept that was laid out by Russel and Burch in Therefore, the search for relevant information about methods compliant with the 3Rs is a key issue of authorization procedures for animal experiments in Europe. The aim of an indispensability search is to proof the lack of the presence of 1 a suitable alternative method according to the 3Rs concept that can be applied instead, 2 usable results from comparable previous animal experiments, and 3 results from other research suited to anticipate the outcome of the planned experiment.
Only when the availability of a suitable alternative or of usable scientific results have been excluded based upon the current state of knowledge, an animal experiment may be authorized. Scientifically relevant databases like PubMed provide the opportunity to search an ever-growing number of documents simultaneously via simple and usually general keywords.
After retrieving the hit list, extensive efforts are usually required for sorting out irrelevant literature. Moreover, the typical curriculum of scientists completely lacks courses in information retrieval. Most scientists may only be capable of applying ordinary searcher skills. In order to support the implementation of animal protection obligations in the sciences, ZEBET advises individual scientists and authorities how to obtain, evaluate, and apply information on suitable alternative methods.
ZEBET follows a three-fold strategy to improve information dissemination on alternative methods to animal experiments that consists of 1 capturing of and supply with information, 2 education in reliable search procedures, and 3 research in retrieval technology. In the basic sciences, the impact of a method is judged by bibliometric analyses, i.
For a more informed evaluation, it is planned to conduct expert consultations whenever a sufficient body of alternative methods addressing a defined topic in the basic sciences has been compiled. The primary objective of the consultations will be to reach consensus on the relevance and the foreseen application domains of the given methods. Currently, the emphasis of the database is on methods in toxicity and potency testing, e.
In the future, the focus will be extended to cover alternatives in the basic sciences more comprehensively. Surveying the relevant literature is part of the daily business in basic science and medicine; however, courses on information retrieval are not obligatory in scientific education. The ZEBET part covers topics of information retrieval like structured searching, choosing the most relevant information resources, conceiving of search terms, using operators and wildcards, index-term-based searching, and semantic search engines.
A main goal of the course is to instruct participants in index-term-based classification searching strategies Motschall and Falck-Ytter , and 3R-relevant terms. They aim to gather the meaning of natural language documents or phrases from the occurrence and co-occurrence of certain terms and their synonyms within the text of a document and thus assist scientists in retrieving and sorting relevant domain literature.
For this assessment, more than scientists at the BfR and also scientists at other federal institutions can be consulted in the evaluation. ZEBET scientists investigate whether the application reflects the latest scientific findings, whether alternative methods exist that can be used instead of the proposed animal experiment, whether the experimental design is statistically sound and, at the same time, whether the number of animals reduced to a minimum without compromising the objectives of the project.
Additionally, scientists who develop or wish to establish new alternative methods in research institutes, universities, or industry also frequently approach ZEBET. Because of their many years of experience in the development, validation, and regulatory recognition of alternative methods, ZEBET scientists are able to judge whether a new alternative method is likely to be a suitable replacement for an internationally established animal experiment and how this goal might be achieved.
ZEBET scientists are also sought as experts on the international level in research support programs for the development of alternative methods and for the judging of research prizes. Furthermore, ZEBET scientists are very popular interview partners for the German media because of their comprehensive expert knowledge. Botulinum neurotoxin testing. Currently, the serotypes BoNT-A and BoNT-B are used as active ingredients in licensed drugs for the treatment of a variety of medical disorders such as cervical dystonia, blepharospasm, spastic conditions, and hyperhidrosis.
Therefore, it is not only a question of potency but also of drug safety that the biological activity of BoNT needs to be determined as accurately as possible. In the case of BoNT LD 50 potency testing, the dosing of animals is associated with severe suffering. Death is generally secondary to respiratory failure due to paralysis of the respiratory muscles. Consequently, the introduction of alternative methods is urgently required. A number of alternative tests have been developed in the past decades aiming to replace the mouse bioassay. Additionally, promising methods are under development, which may alone or in combination with other assays meet the rigid requirements of potency testing.
In this context, no standard validation program can be applied, but individual validation plans have to be developed. Experts from industry, regulatory authorities, German ministries, academia, national and international validation centers, and animal welfare organizations were invited to actively participate in the meeting. During the meeting it became clear that guidance on product-specific validation of alternative methods to the LD 50 potency test needs to be given by the regulatory authorities in close communication with the manufacturers before and during the validation process.
To facilitate validation efforts, international harmonization and mutual acceptance criteria of regulatory authorities are necessary. Importantly, funding should be made available and coordinated to develop and validate alternative assays for BoNT potency testing according to the 3Rs principles.
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Especially the development of a replacement alternative for BoNT testing should have priority. At the expert meeting, researchers and industry could demonstrate some progress in implementing reduction and refinement in BoNT potency testing, and in the development of alternative potency assays.
Furthermore, the BoNT EWG should promote awareness and transparency between the stakeholders and regulatory authorities. Additionally, experts from overseas are invited as observers. However, the outcomes of the meetings remain confidential unless otherwise expressly agreed by all members. Implementation and enforcement of the 3Rs principle in the field of transgenic animals. However, building on our strengths, such as boosting collaborations and networking in the national as well as the international arena, and intensifying our efforts at the OECD level, will remain a central future aim.
Also, the existing expertise in in vitro methodologies as alternatives to animal testing needs to be fairly expanded, and research efforts especially regarding chronic toxicity endpoints increased. In particular with regard to chronic toxicity endpoints, such research efforts are still ill funded and scattered throughout Germany and to increase exchange and collaboration a National Reference Center for Alternatives to Animal Testing should be established which could be hosted at ZEBET BfR.
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author s and source are credited. Skip to main content Skip to sections. Advertisement Hide. Download PDF. Alternatives to animal testing: current status and future perspectives. Open Access. First Online: 24 May On the future of ZEBET Some general considerations and thoughts While finalizing the schedule and program of the 20th anniversary symposium, ZEBET staff were highly interested in discussing the possible future direction of the department in order to provide a proposal on how the future of ZEBET might look like, as a milestone not too far away, let us say—maybe in the forthcoming one or two decades.
One of the main tasks of ZEBET is to collect all available information on alternative methods to animal testing and to provide an up-to-date science-based assessment to its stakeholders. ZEBET is also pursuing in-house research and develops modified or new bioassays that would be suitable to replace animal experiments or to reduce animal numbers subjected to particular in vivo assays. At the same time, ZEBET is pushing for validation of alternative methods developed through our own efforts or by any other research group or consortium dedicated to establish alternative methods.
Open image in new window. To fulfill all of these tasks, ZEBET is organized in three basic albeit overlapping units dedicated to documentation, evaluation, and research Fig. Being subdivided into a set of different departments, the portfolio of the BfR encompasses the areas of biological safety, food safety, chemicals, and product safety, as well as risk communication.
All of these departments have proved important and instrumental in supporting the work and goals of ZEBET ever since the BfR has been established in Incorporating ZEBET into the larger institution of the BfR holds great promise and offers a range of advantages mainly resulting from the interdepartmental and interdisciplinary interactions. This has occasionally resulted in unexpected progress and success with some of those innumerable activities and engagements initiated by ZEBET.
Still, there is further and as yet untapped potential of this structure awaiting to be fully utilized and gainfully applied for the sake of both human health and animal welfare. A total of about The share of animals used for toxicology and safety evaluation dropped from 9. Despite the increase in reporting countries, this amounts to nearly 40, animals less used. However, the total number of animals used increased by 3. Similarly, there is a steady increase of animal usage in Germany in the last decade, in part due to rising numbers of transgenic animals and animals killed without prior experimentation for organ and primary cell harvesting Kretlow et al.
A second large fraction of These numbers are an economic as well as an ethical call for alternative methods replacing animal testing. These efforts will be described in more detail below. The first toxicological consideration is that of exposure. Every living being has some form of barrier to protect it from environmental stresses and impacts Fig.
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For the human body, the main barriers are the skin and the mucous membranes. The first possible routes of exposure are therefore skin penetration, inhalation, and exposure of the respiratory tract, as well as ingestion and exposure of the gastrointestinal tract. A number of in vitro models are commercially available as three-dimensional tissue reconstruction models Pampaloni et al. Some examples are epidermis, full-thickness skin models, respiratory epithelia, keratinocyte eye cornea, vaginal epithelia, and oral epithelia.
Blood-tissue barriers form a second line of defense, the most prominent of which are the blood—brain barrier and the placental barrier; and the blood—brain barrier has been modeled in vitro Stolper et al. The advance in three-dimensional models has also allowed for internal organ models Pampaloni et al. However, the adult human body presents with about 40 different organs composed of at least cell types Fig. To reconstruct all human tissues, in vitro would be a formidable task today, and toxicological testing on all separate tissue models would put even the direst estimates of animal use in a temporally and economically favorable light.
How then can we achieve an idea of the systemic toxicity of substances without animal use? A promising approach is computer-aided modeling of the systemic behavior of a substance, so-called in silico methods. The physiology-based pharmacokinetic PBPK model integrates information from different in vitro and in silico quantitative structure—activity relationship [ Q SAR] approaches and predicts the systemic availability of a compound under certain exposure conditions and hence allows to evaluate the toxicological relevance of an in vitro derived toxic concentration Verwei et al.
An approach to predict the target effects of a substance is the Connectivity Map Fig. Here, mRNA expression profiles are collected in a database of a range of different cell lines exposed to substances with known mechanisms under a small number of defined conditions. This limitation to ubiquitous cellular pathways is a necessity since expression profiles themselves are already large datasets. The expression profile in response to a new substance is then compared to the signature database, and by similarity a mode of action, including off-target effects, can be predicted Fig.
Toward international acceptance of alternative methods Already in , an international committee under participation of ZEBET convened to develop a scientific concept for the experimental validation of toxicological testing methods Balls et al. Followed by two similar workshops Balls et al. This process not only contributed to the successful validation and international recognition of alternative methods for toxicological hazard identification tests but also established that the agreed principles of validation hold for any new and updated test method, whether it is an in vivo or in vitro method, and both for ecotoxicity tests as well as for human health tests.
In addition, this exemplifies the long process of introducing new OECD guidelines, which is in part due to the fact that a unanimous consensus has to be found. An internationally harmonized testing helps companies and their products to be competitive in the global marketplace in addition to preventing unnecessary repeated testing on live animals or in vitro. These test systems either utilize whole embryos or dissociated cells from embryos Piersma In recent years, stem cells have been the subject of increasing scientific interest because they represent an important new tool for developing unique in vitro model systems.
They also have great potential to predict or anticipate compound-triggered toxicity in vivo. Stem cells are capable of self-renewal, that is, they can be continuously cultured in an undifferentiated stage, giving rise to more specialized cells such as heart, liver, bone marrow, blood vessels, pancreatic islets, and nerve cells upon addition or removal of certain growth factors [Fig.
This so-called embryonic stem cell test [EST; Spielmann et al. As an in vitro system which mirrors both proliferation and differentiation, the EST proved in an international European Centre for the Validation of Alternative Methods ECVAM validation study to be a reliable assay for the prediction of embryotoxicity in vivo Genschow et al. In Germany, this is the only program that provides sufficient financial support for the cost-intensive and time-consuming process of validation.
Evaluation of value-added databases represents the most reasonable starting point for any structured search for information Emmerich The documents in the database are written in a structured and standardized manner and focus on the most essential facts of the listed alternative methods. The added value of these documents is constituted through expert selection of the incorporated literature, committed to the most substantial and reliable information only, and a subsequent stringent peer review process including scientists with complementing in vivo and in vitro expertise.
Composition and phrasing of the method summaries are standardized to enable immediate orientation and easy comprehension, and to provide the possible feedstock for up-to-date text mining applications. Here, users will find highlighted facts to consider, the specific objective that can be addressed by employing the method at hand, the state of development, its acceptance in the scientific and regulatory communities, its application domain, and its contribution to the 3Rs concept. The main text of the method summary aims to cover all aspects necessary for understanding the suitability and applicability of the method with a focus on practical considerations.
It is the worldwide first tool of its kind specially equipped with expert domain knowledge from the area of the 3Rs. When a user performs a search query with Go3R, the search engine compares the concepts of the ontology with the vocabulary used in the retrieved documents Sauer et al.
The beta-Version is available online free of charge Fig. An essential extension will be the inclusion of scientific resources other than PubMed.
Go3R thus may be used to assign 3R-relevant index-terms to unstructured natural language documents in retrospect automatically. ZEBET staff members share their knowledge with scientists, competent authority staff, animal welfarists, and other interested persons in a number of ways. Botulinum neurotoxin BoNT is a biological product released by the anaerobic, gram-positive bacterium Clostridium botulinum. There are seven major and serologically distinct serotypes of BoNT, characterized by a complex mode of action which results in a blockade of acetylcholine release at neuro-muscular nerve endings leading to flaccid paralysis Fig.
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This mechanism of toxicity comprises at least three stages of binding, internalization, and proteolytic cleavage of a substrate, which leads to inhibition of synaptic exocytotoxic transmitter release. Different serotypes of BoNT act on different substrates. Therefore, our future efforts have to go beyond improving and extending what is already established, both regulatorily and experimentally cf.
With the realization that testing and experimentation on animals will be indispensable for some time to come grows the importance of the aspect of refinement Fig. Research into refinement is still on the sideline, but it has been shown already that enriched environments for laboratory animals improve the reliability of test results Cao et al.
Most importantly, it would allow for training of veterinary surgeons and staff involved in animal experimentation, which will ideally become a mandatory part of their curriculum. In September , the European Parliament adopted the revised Directive on the protection of animals used for scientific purposes. The new Directive will take effect on January 1, Directive Conflict of interest The authors declare that there are no conflicts of interest. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author s and source are credited.
Altern Lab Anim — Google Scholar. Balls M Defined structural and performance criteria would facilitate the validation and acceptance of alternative test procedures. Mouse pups Credit: PA Photocall.
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Figures for show numbers of animals that completed procedures, as declared to the Home Office using their five categories for the severity of the procedure. Oxford also maintains breeding colonies to provide animals for use in experiments, reducing the need for unnecessary transportation of animals. Figures for show numbers of animals bred for procedures that were killed or died without being used in procedures:. Primates account for under half of one per cent 0.
They are only used where no other species can deliver the research answer, and we continually seek ways to replace primates with lower orders of animal, to reduce numbers used, and to refine their housing conditions and research procedures to maximise welfare. However, there are elements of research that can only be carried out using primates because their brains are closer to human brains than mice or rats.
Some are used in studies to develop vaccines for HIV and other major infections. Primate in lab Credit: OU. The primates at Oxford spend most of their time in their housing. They are housed in groups with access to play areas where they can groom, forage for food, climb and swing. Primates at Oxford involved in neuroscience studies would typically spend a couple of hours a day doing behavioural work.
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This is sitting in front of a computer screen doing learning and memory games for food rewards. No suffering is involved and indeed many of the primates appear to find the games stimulating. They come into the transport cage that takes them to the computer room entirely voluntarily. After some time a period of months demonstrating normal learning and memory through the games, a primate would have surgery to remove a very small amount of brain tissue under anaesthetic.
A full course of painkillers is given under veterinary guidance in the same way as any human surgical procedure, and the animals are up and about again within hours, and back with their group within a day. The brain damage is minor and unnoticeable in normal behaviour: the animal interacts normally with its group and exhibits the usual natural behaviours. In order to find out about how a disease affects the brain it is not necessary to induce the equivalent of full-blown disease.
Indeed, the more specific and minor the brain area affected, the more focussed and valuable the research findings are. The primate goes back to behavioural testing with the computers and differences in performance, which become apparent through these carefully designed games, are monitored.
At the end of its life the animal is humanely killed and its brain is studied and compared directly with the brains of deceased human patients. Primates at Oxford involved in vaccine studies would simply have a vaccination and then have monthly blood samples taken. Housing for primates Credit: PA Photocall. Figures up to and including were recorded when procedures began.
Figures from are recorded when procedures end. Primates macaques at Oxford would typically spend a couple of hours a day doing behavioural work, sitting in front of a computer screen doing learning and memory games for food rewards. This is non-invasive and done voluntarily for food rewards and does not count as a procedure. After some time a period of months demonstrating normal learning and memory through the games, a primate would have surgery under anaesthetic to remove a very small amount of brain tissue.
The primate quickly returns to behavioural testing with the computers, and differences in performance, which become apparent through these carefully designed puzzles, are monitored. Numbers vary year on year depending on the research that is currently undertaken. In general, the University is committed to reducing, replacing and refining animal research. There are very many non-animal research methods, all of which are used at the University of Oxford and many of which were pioneered here.
These include research using humans; computer models and simulations; cell cultures and other in vitro work; statistical modelling; and large-scale epidemiology.
Methods of Animal Experimentation
Every research project which uses animals will also use other research methods in addition. Wherever possible non-animal research methods are used. For many projects, of course, this will mean no animals are needed at all.
For others, there will be an element of the research which is essential for medical progress and for which there is no alternative means of getting the relevant information. As the Department of Health states, research on animals has contributed to almost every medical advance of the last century. Without animal research, medicine as we know it today wouldn't exist. It has enabled us to find treatments for cancer, antibiotics for infections which were developed in Oxford laboratories , vaccines to prevent some of the most deadly and debilitating viruses, and surgery for injuries, illnesses and deformities.
Life expectancy in this country has increased, on average, by almost three months for every year of the past century. Within the living memory of many people diseases such as polio, turberculosis, leukaemia and diphtheria killed or crippled thousands every year.